An article published on line last year in Anticancer Research has just come to our attention. It puts forward the relatively simple proposal that by combining androgen deprivation therapy (ADT) with estrogen deprivation therapy (EDT) we might be able to significantly impact the risk for development of castration-resistant prostate cancer (CRPC).

The original full text article by Sinha et al. from the Minneapolis VA Medical Center is based on laboratory studies using tissue from biopsy specimens taken from untreated and diethylstibestrol (DES)-treated patients. (Sinha has also written a “Beyond the abstract” commentary about this paper on the UroToday web site.) Their suggestion is effectively that there are at least two critical populations of cells involved in the development of prostate cancer over time: androgen-dependent light basal cells and estrogen-dependent dark basal cells, and by treating both types of cell we may be able to seriously impact cancer progression.

We know that ADT is able to block temporarily the development of the androgen-dependent cancerous basal calls (for greater or lesser periods of time in individual patients), but that it has no impact on the estrogen-dependent cancerous basal cells. Sinha et al. therefore argue that it is an “incomplete” form of treatment and that the continuing presence of estrogen-dependent cells may be key to the development of CRPC. Sinha and his colleagues go on to suggest that concurrent androgen and estrogen ablation, together with the inhibition of selected steroid biosynthetic enzymes, may be able to have a greater therapeutic impact on progression of prostate cancer over time.

Now the interesting thing about this hypothesis is that, by comparison with other ideas, this would be relatively easy to test because there is already a variety of antiestrogenic agents available, so we don’t need to go out and create new drugs to investigate this idea.

It is unclear whether it would be appropriate to implement this strategy in humans yet. Some more careful laboratory work and perhpas some equally careful animal studies may be necessary before anyone was willing to try this in man. And your sitemaster is neither a pharmaceutical biochemist nor a research endocrinologist, so his knowledge of the feasibility of a strategy like this is limited in the extreme. However, it sounds like an interesting idea that might well be worth exploring further (which only takes money, of course).

The other thing that such a form of therapy probably wouldn’t be able do is “cure” prostate cancer. Cancer, like infectious diseases, has a phenomenal capacity to become resistant to treatment in all sorts of interesting ways … but if it could delay the onset of CRPC by a meaningful period of time (a year or more) in the majority of patients with progressive disease, that could be a big deal.

And last but not least, it has not escaped the authors’ attention that is this works in prostate cancer it may also work in breast cancer, by the reverse process of addition of ADT to standard forms of EDT.

17 Responses

Note the date when the tissue samples were collected. This is weirdly dated data. The original pathologist on the study was Gleason, of the Gleason score. As an anatomist, I found the black and white images in the original paper impossible to interpret with confidence. Did you see those figures? Could you figure them out?

Also it should be clear that transdermal estradiol (a modern ADT protocol) and DES used in the paper are not the same agents nor similar estrogens.

I’ll now go back and reread the original paper, but I had a hard time making sense of it when I first read it.

Yes, I had noted all of that. However, the hypothesis is still interesting, and it really wouldn’t be hard to test.

The assiduous preclinical scientist would probably argue, with a high degree of validity, that this shouldn’t be tried in a human until more studies had been done in the lab — and perhaps on tumors in mice/rats.

It’s worth at least a quick look — scientifically — to see if it has any merit. DES may be a little hard to come by today, but it’s not exactly hard to synthesize for testing purposes. And maybe the concept would work just as well if one used ADT + transdermal estradiol. As I said, I am not a pharmaceutical biochemist or a endocrinologist.

Frankly, my head spins whenever I look at the role of estrogen and estrogen receptors (ER) in prostate cancer development.

There are two main ERs (ERα and ERβ). ERα stimulates growth of cancer and ERβ slows its growth (so estrogen is both an agonist and antagonist) in early stages, but that all changes as the cancer develops. And, in the pituitary, an ERα agonist stops testosterone production. This was the basis for the anti-cancer drug, Capesaris (for a discussion of this with Evan Yu, see this link.

This information on the effect on basal cells complicates the picture still further. This only applies to tissue within the intact prostate and not to metastases. Perhaps it adds to the argument for debulking the prostate when there are known metastases. Then, estrogen patches can be used without fear of encouraging cancer development within the prostate.

I found his commentary highly alarmist in tone and uninformed of progress, but more on that below. I did check his publications on prostate cancer and was a bit surprised to find that he is well published, which would suggest he should be knowledgeable. Here are some fundamental concerns I have about the concept of adding an anti-estrogen to ADT to combat prostate cancer.

Dr. Sinha’s paper apparently conveys this view: “We know that ADT is able to block temporarily the development of the androgen-dependent cancerous basal calls (for greater or lesser periods of time in individual patients), but that it has no impact on the estrogen-dependent cancerous basal cells.” How do we know this? On the contrary, I believe we know that decreasing testosterone via ADT also decreases estrogen because estrogen is made from testosterone. In fact, one of the reasons those of us on long term non-estrogen based ADT (the predominant form in the US these days and for many years), like I was for 14 years intermittently, need to take medication to counteract loss of bone density because we are decreasing the source of male estrogen — testosterone — upon which bone density depends. That typical decrease of bone density at least suggests that typical non-DES type ADT decreases estrogen.

Sitemaster, isn’t your following comment the exact opposite of the proposed concept: “And maybe the concept would work just as well if one used ADT + transdermal estradiol.” That approach is ading estrogen rather than deleting it. I am familiar with that approach as I was on it instead of a bisphosphonate drug to protect bone density (worked very well) for my fourth round of ADT (18 months ending in April of 2014).

Regarding the tone of Dr. Sinha’s commentary, I find several statements alarmist and not based on fact. He states: “War on Cancer: Success or Failure?. Since the declaration of the War on Cancer by President Richard Nixon in 1971, progress on controlling and treating prostate cancer has been dismal.” Actually there has been exciting progress, especially recently, and very definitely great progress against prostate cancer. Evidence is well summarized in the Progress Report for 2015, published by the American Association for Cancer Research. More evidence is present in the American Cancer Society’s Statistics for Cancer 2017, which was published days ago.

Similarly, his commentary states: “Since 1971 nearly every solid organ cancer has increased in the United States and in the world. Using PC as a case study, our objective was to describe how we have effectively lost the War on Cancer. Similar case can be made for cancers of breast, colon, lung, brain, and pancreas.” With bologna this huge he needs to open a deli. Can anyone help me understand how anyone can look at the death rate graphs for prostate, breast, colon and lung cancer and not be encouraged by the striking progress that has been and is being made? How can a responsible doctor assert such things?

Richard, I know these issues are right in your ball park, and I look forward to your comments.

(2) I am far less impressed than you seem to be with the “progress” in the “war” on cancer. I think an enormous amount of money has been spent on an awful lot of rather poor research.

(3) Trying things that are “different” (even when they may not seem to be “logical” to most of the research community) has always been where the greatest progress has come from.

(4) If Dr. Sinha is wrong (which he very well may be) it will cost us peanuts to find that out. But if Dr. Sinha is right and we ignore his idea, then where will we be?

You sound very like all the people who told Barry Marshall he’d never be able to cure gastric ulcers with a very commonplace antibiotic. They were wrong. And Barry has a Nobel Prize to prove it. Better still, almost all gastric ulcers are now curable without the truly ghastly forms of surgery and other treatments that were still being imposed on people in the 1980s and 1990s.

But what about the issue — decreasing testosterone via non-estrogen types of ADT, in other words the usual types in the US, also decreases estrogen, enough to cause bone density risks after many months of use if not countered. Thus, customary ADT already reduces estrogen at least enough to have a clinically undesirable effect, which Dr. Sinha seems to ignore. That point has not yet been addressed.

Regarding progress against cancer, have you looked at the graphs for progress against cancer that were just published? I’m using the “analysis tools” option for Trends in death rates — 1930 through 2014 at the ACS site mentioned in my initial comment. These graphs track death rates by year for various cancers per 100,000 persons, giving precise results if you rest your cursor on any point on the graph. At least the graphs for prostate, breast, colon and lung cancer show dramatic (and continuing) reductions:

— For prostate cancer, the difference between 1993 (39.3 deaths per 100,000, age adjusted) -– the high point of the death rate from prostate cancer — and 2014 (19.1) is 20.2, which amounts to a reduction of 51%! How can anyone not consider that as dramatic progress?

— How about Male Lung and Bronchus: 91.1 at the high point in 1990, but a constant decline to 52.1 in 2014, a reduction of 39 deaths per 100,000, which amounts to a reduction of 43% with a nearly constant rate of decease over the past 24 years, which is promising.

— We see a similar thing with male colorectal cancer: from a high of 34.2 in 1980, a fairly steady downward trend to 17.3 in 2014, a drop of 50%.

— Finally to round out the big four, female breast cancer declines from a high of 33.1 in 1990 (a remarkably steady rate since 1930, which was only slightly lower) to a rate of 20.5 in 2014 after a steady rate of decline from the high point. That’s a decline of 12.6 deaths per 100,000, which amounts to a reduction of 38%.

Try comparing that to the progress we have made against HIV/AIDS or hepatitis C and perhaps you will see why I am not as impressed as you are. In both cases we have gone from them being nearly 100% fatal diseases in the relatively short term to either decades-long survival or absolute elimination of the disease in the majority of patients. It’s not hard to put a positive spin on the progress we have made against cancer, but it is the lack of progress that led to the formation of Stand Up for Cancer and the current Moonshot … and both those initiatives have helped but the vast majority of metastatic cancers are still incurable. And most of the progress in lung cancer came from the simple process of getting people to just stop smoking.

It reports that DES was shown back in 2001 to have a significant apoptotic effect on prostate cancer, of 5-8 months duration, but it involves considerable cardiovascular toxicity. It also suggests that the mechanism may involve the role of DES in suppressing androgen production from extratesticular sources.

The possible roles of DES in treatment of prostate cancer is actually quite well understood when used as a single agent. And the cardiovascular toxicity of DES is highly dependent on the dose being used. Back in the 1960s and 1970s, dosing with DES at 5 mg/day was quite common. That does level is indeed associated with a high risk for cardiovascular side efffects. Lower does of DES (e.g., 1 mg/day) appear to be associated with fare les fisk for cardiovascular side effects but seem to have similar clinical effects on prostate cancer.

The current problem with DES is that it is no longer made commercially in the US, and so actually being able to get hold of it to use as a form of treatment is extremely difficult.

I believe that one can still get DES, even though it is not manufactured in the USA. I would say instead that the “current problem with DES is that it is…” an oral estrogen and as such, even at the lower dose carried a blog clot risk. One would be safer to go with the natural estrogen in men, namely estradiol and to take in transdermally. See the PATCH study papers.

Assuming I am, I have now gone back and looked at Dr. Sinha’s UroToday essay and the original paper. I see problems with both. As I mentioned earlier, this is strangely ancient work that has been resurrected. The micrographs published in the origin Anticancer Research paper are not of a quality that one could expect to publish in a high quality journal today. They may or may not show what Sinha writes about, but they are not good enough to tell, and the staining is not what most cell biologists study cancer would use today.

The Sinha et al. paper is in a journal with an Impact factor of 1.8. That is quite low for a journal publishing on prostate cancer (although I’ll admit that Ive published quite a few papers in my career in journals with impact factors below that).

Sinha’s anti-estrogen case in part is not well laid out, nor up to date. Or so I believe. Abiraterone crashed a patient’s T as well as his E. So we already have a drug that addresses that issue.

Sinha talks about watchful waiting, not active surveilance. It is language like that that makes the paper seem like it came out of the distant past.

The UroToday essay has too many sweeping generalization that I can not completely agree with.

In sum, I am not sold on Sinha’s argument. I would like to see this research redone with modern stains and will cells exposed to estradiol, not DES.

That said, Sinha is a well recognized scientist. In the early 1970s he was an explorer and he even has a mountain named after him.

And thank you Sitemaster, as always, but especially for your report of January 6 on the statistics for prostate cancer, which I did not read until yesterday. I fully agree, of course, that a lot more needs to be done, especially for metastatic patients. Winston Churchill’s famous remark following great and long awaited success during World War II in Africa in 1942 comes to mind:

“Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.”

We can make a strong argument that we are even further along than that!

I think this is the first time we’ve been in direct contact, but I very much like your professional synopses on this site.

Capesaris, as far as I know, has not survived clinical trials, nor did it make much sense to me. I haven’t though asked the folks in Seattle for an update.

Meanwhile the data keep coming in that, for hormone sensitive prostate cancer, high dose parenteral estradiol is as good as the LHRH agonists … and is as safe.

As for the dangers of activating the alpha vs beta E receptors, the situation is indeed very complicated since estradiol (E2) can regulate its own receptor density and presumably receptor ratio density (which can surely make one’s head spin). However, if one reduces this to what it might mean in a clinical setting for patients, my non-MD sense is that transdermal estradiol is a good alternative to LHRH agents, provide a patient: (1) is not castrate resistant, (2) can tolerate gynecomastia, (3) doesn’t have a family history of BRCA-driven breast cancer, and (4) can believe that a natural hormone may be as good for him as an expensive synthetic hormone — even though it costs an order of magnitude less.

The benefit would be in side effects; i.e., other than the gynecomastia, the E2 protects the patients from hot flashes and osteoporosis. It may have other benefits as well. That said, the moment the prostate cancer becomes castrate resistant, I’d get off the stuff. Anyway, that was my recommendation to the PATCH folks when they asked me about it around a decade ago.

Note: I should be seen as biased here. Although I carefully do not promote E2 for ADT in the ADT book, I have been on intermittent E2 myself for ADT for close to 18 years and my PSA is currently undetectable. Also I now publish with the PATCH folks, so I could be considered biased in that regard as well.

I’m a fan of yours as well. I often share your Tikkun article with men who feel diminished by lack of libido. In the link I provided, Evan Yu was hopeful that clinical trials on Capesaris would continue, but that does not appear to have happened. I think there will be an update of the single ongoing trial NCT01615120. I think estrogens, when given to men, should include 10 mg daily tamoxifen to prevent gynecomastia.

The Tikkun article was invited, but I never imagined an MD would be giving it out to patients. Admittedly, I do occasionally publish personal essays, but they are contrived as narrative therapy for me and not meant to be therapeutic intervention for others. You can pull up the latest one at:

On giving tamoxifen to prostate cancer patients starting on ADT, I was wondering what was known about the long-term effects and I couldn’t find a clear review of that. So Dr. Erik Wibowo (my post-doc) and I did one. Here’s the citation:

I have responded to the comments on our article. If I have missed a point or two, I would be happy to address those.

Prostate cancer has at least two types of cancers; one is dependent on androgen and the other on estrogen. Androgen ablation therapy has been used for over 70 years. It induces cell death in androgen-dependent cells, but leaves estrogen-dependent cells to proliferate and repopulate the prostate resulting in castration-resistant prostate cancer. In our opinion, antiestrogen therapy, such as tamoxifen, may be the best treatment to address CRPC. Abiraterone is a partial antagonist to androgen receptors and an agonist for estrogen receptors. This therapy is an incorrect treatment for CRPC. The manufacturers of abiraterone have sold a bill of goods (see later). We have not investigated the role of progesterone in prostate cancer and are unable to comment on that. I have addressed that in the article.

I would say that any institution that conducts a limited clinical trial would become a destination for the treatment of CRPC. I am talking with several groups in Minnesota as well.

If you like, you can publish the comments and my response.

Sincerely yours,

Akhouri A. Sinha

Now follows my response:

1. Response to Dr. Richard Wassersug

I am enclosing my earlier publication that has dates of samples and analysis of data that was published in 1977. This paper includes light and electron microscopic study (ref. #1). This 1977 paper also shows dark basal cells in untreated prostate (Figs. 1, 2), but their numbers increased in DES-treated cases (Figs. 10, 11, 12). The light and dark cells can be clearly seen in black and white micrographs, including localization of immunogold particles as shown in our Anticancer Research paper. I regret that Dr. Wassersug had difficulty in deciphering our figures. Reproduction of micrographs could have been improved by photoshop, but that was not under our control.

We have not discussed transdermal estradiol in the paper. DES was given to patients at the VA and it was used by Charles Huggins. Our study was an adjunct to the VACURG study. We have described the findings of VACURG on page 3148 of the Anticancer Research paper, 2016.

2. Response to Sitemaster, on January 7, 2017 at 1.49 pm

I agree that our hypothesis can be tested easily.

Our hypothesis should be tried on CRPC patients. There are no animal models with CRPC cancer. We have studied LNCAP and Du 140 tumors in nude mice. We had implanted human prostate pieces in nude mice prostate that grew a week. We localized PSA (prostate specific antigen) in tumor sections. We discontinued the study for the lack of funding. We have studied PC-3 prostate cells in mice. We also studied Dunning rat tumors. Some of them were published and others were not. We concluded that none of the animal models were suitable to study CRPC tumors.

We studied biopsy samples of patients as outlined in Ref. # 1. Using untreated and DES-treated cases, we analyzed data and determined CRPC tumor.

DES was used in androgen ablation until the 1970’s.

We have advocated for ADT ablation and estrogen ablation followed by inhibition of some biosynthetic enzymes. Estrogen ablation can be accomplished by antiestrogen drugs, such as tamoxifen. Tamoxifen is an FDA-approved drug for breast cancer and male breast cancer, but not for prostate cancer or CRPC tumors. One could get FDA approval for CRPC tumors. The reason tamoxifen is not approved for prostate cancer is not known. Until our paper, no one had shown the presence of estrogen-dependent cells in prostate cancer.

We estimate that 80-90% cells are androgen-dependent and ADT works well on them. About 10-20% cases have estrogen-dependent cells. The ADT treatment frees estrogen-dependent cells to proliferate and populate the prostate when androgen-dependent cells are depleted. These cells cannot be identified in homogenized tissue. One has to isolate them by laser capture dissection, a labor-intensive process.

Androgen, estrogen, and progesterone proteins and their receptors have been shown in human and animal prostates and human and animal breast tissues. We have not studied progesterone receptors.

A brief review shows that the steroid biosynthetic pathway progresses from cholesterol to pregnenolone to progesterone to testosterone to estradiol. These steps are catalyzed by a variety of specific enzymes. There is an alternate pathway for estradiol biosynthesis via dehydroepiandrosterone. The authors are not trying to educate you in steroid biosynthetic pathway, but are trying to show that estrogen can come from another pathway. Furthermore, androgen ablation is never complete. Earlier efforts for complete androgen ablation by adrenalectomy and hypophysiectomy were not achieved. Estrogen is available from phytoestrogen in the food we eat.

In embryos the basis format of the fetus is female and it becomes male format when testosterone is available to the fetus.

3. Response to Jimwaldenfels, on January 7, 2017 at 7.57 pm

We are not surprised by his comments. He shows the androgen ablation bias that has existed for about 125 years and this bias is not going to go away from one paper. There are over 30 drugs now FDA approved for androgen ablation, but none for estrogen ablation in the prostate.

Abiraterone acetate: This drug is is a synthetic, steroidal CYP17A1 inhibitor used in the treatment of castration-resistant prostate cancer. The drug has been found to act as a partial antagonist of the androgen receptor and as an agonist of the estrogen receptor. Abiraterone has recently been found to act as a direct agonist of the estrogen receptor. It induces proliferation in human breast cancer cells. This drug partially inhibits aromatase and thus estrogen. Please see New Engl J Med. 2011;364:1995-2005,and Nature. 533 (7604):547-551. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is more abundant than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression (see Nature 533 (7604):547-551). How this drug received FDA approval is beyond my imagination. This drug also promotes cancer progression. This drug is FDA approved and is given with prednisone. Progression-free survival was 5.6 vs. 3.6 months. The survival can vary with individual patients. The drug has numerous side effects. Our comment is that abiraterone acetate is an incorrect choice for treatment of CRPC because it promotes estrogen receptor and proliferation in breast cancer. This situation is not different when androgen ablation destroys numerous androgen-dependent cells, thereby liberating estrogen-dependent cells which proliferate after DES treatment. It is for these reasons we have advocated estrogen ablation by an antiestrogen drug, such as tamoxifen or similar drugs.

Maybe Jimwaldenfels can educate me too: Why has prostate cancer not been cured after huge amount of efforts by so many for so long? Why does the prostate develop cancer frequently, but seminal vesicle infrequently? Embryonic origin is from the same general area of the urogenital sinus.

ADT ablation does not have the capacity to block estradiol. It may temporarily reduce estradiol until estradiol is synthesized by an alternate pathway or becomes available from phytoestrogen.

We would not comment on bone density etc.

We have put forward a hypothesis and provided evidence to support it.

Jimwaldenfels further states that the author’s statement and tone on the war on cancer is alarmist, and that great progress has been made on prostate cancer. Has any prostate cancer been cured? Has any breast cancer been cured? The same question can be asked for many other solid organ cancers. We stand by our analysis of data between 1971 and 2014.

4. UroToday essay

Cancer data were analyzed using “Cancer statistics” in 1971 by Edwin Silverberg and Arhur Holleb published in CA Cancer J. Clin. 1971;1:13-31 and “Cancer statistics, 2014” CA Cancer J. Clin. 2014;64:9-29. Footnote states that 62,570 in situ carcinomas of the breast were not included in the statistics and some other cancers were also excluded. Similar exclusions were not made in 1971. Jimwaldenfels can analyze data between 1971 and 2014. Sometimes generalization makes a point that is lost in details. We encourage you to analyze and update our data including study of 2017 paper. We would love to read your updated data and study. The ACS does not count all cancers. The author has given the figure. Our effort to seek clarification fell on deaf ears. The authors are glad that you rested your case at 9.24 PM. It is about time.
Comments like “hot air”, “bologna”, and “open a deli”, are not part of civil (or civilized) discourse. They do not merit further discussion.

Both prostate and breast cancers have increased between 1971 and 2015

5. Response to Sitemaster, on January 7, 2017 at 8.36 pm

Sinha is a reproductive biologist and embryologist not a clinician. We agree that huge amounts of money have been spent on ADT treatment and there is so little to show for that effort. Numerous patients have died because of incomplete treatment of prostate cancer.

We are aware that there are numerous skeptics to our work. It would` take time to sink in to the minds of clinicians and patients. ogma is more powerful and only time would prove whether we are wrong or correct. Changes in medicine and science come slowly. We expect that acceptance of our work would be slow as well. Criticism of our work is no different than those hurled on Dr. Barry Marshall.

Tamoxifen is a treatment for CRPC: The treatment should begin at the first sign of CRPC before any other chemotherapy. ADT would reduce androgen-dependent tumor volume and that would make estrogen-dependent cells for tamoxifen. These cells would show cell death as the ADT treated cells.

7. Response to Sitemaster January 8, 2017 at 7.43 am

You have rested and your comments are like a scientist. We are not dogmatic and our effort may lead to additional progress. We believe that the Sitemaster has a more open mind.

8. Response to Patient on January 8, 2017 at 9.49 pm

We have reviewed the Veteran Administration Cooperative Urological Research Group (VACURG). The study actually found that DES treatment (specifically at 5 mg) was associated with significant cardiotoxicity. In general the conclusion was that 3 mg was the best choice for most patients. We have reviewed this study in our paper. There are now many drugs for androgen ablation.

9. Sitemaster:

The sitemaster has replied to the patient’s query adequately.

10. Ricahare Wassersug:

The authors do not have to add to this point.

11. Richard Wassersug:

The current Anticancer Research paper is a follow-up to a study that was published in Cancer in 1977, a copy of the summary is enclosed. Our paper was presented as an abstract in 2014 at the American Association of Cell Biology and also at the Anticancer Research meetings in Greece in 2014. They are cited on page 3847.

Surveillance is consistent with the current technology terms. Watchful waiting is still a valid phrase. We should have put this term in parenthesis.

We recommend that Dr. Wassersug conducts a new set of studies with “modern” stains. Methylene blue stain is still used on resin-embedded sections. Immunogold localization is current and modern too. These are judgements of individual investigators.

Our study is complex, yet was well understood by Dr. Wassersug and by Urology Today and The “New” Prostate Cancer InfoLink. Presentation of data and results differ between researchers.

This study was done to compare the ultrastructural features of prostatic cancer cells in both untreated and estrogen-treated responsive and refractory patients. Analysis of previously untreated and estrogen-treated carcinomas showed thatthe tumors possessed well- and poorly-differentiated acini, and invasive cells. Malignant acini contained numerous columnar (secretory) cells in untreated, but few in treated individuals. Two distinct types of basal cells were observed in untreated and treated acini: type I (light) and type I1 (dark) cells. In both untreated and treated tumors, type I cells were characterized by having round nuclei with many small aggregates of euchromatin, large nucleoli, and electronlucent nucleoplasm. The type I1 cells had highly pleomorphic nuclei, folded nuclear envelope-sometimes deficient in localized areas, euchromatin, many
small aggregates of heterochromatin, large pleomorphic nucleoli, and relatively electron-opaque nucleoplasm. In some sections, both types of basal cells penetrated through the acinar basal lamina and became invasive. Prostatic carcinomas
which were or subsequently became refractory to estrogens showed more abundant type II basal cells than responsive patients. It is postulated that the type I1 basal cells as well as some type I basal cells are endocrine unresponsive from the outset. Furthermore the tumor possesses a heterogeneous population of cancer cells. While androgen-dependent tumor cells such as columnar cells may be destroyed by endocrine therapy, these endocrine unresponsive cells continue to proliferate, metastasize, and kill the patient. Therefore, we suggest that patient with advanced prostatic carcinoma initially may be given endocrine therapy to reduce tumor burden caused by endocrine-sensitive cells. In addition, early treatment with chemotherapy or radiation may be used to destroy unresponsive endocrine-insensitive cells, before these cells lines have a
chance to proliferate and to develop into refractory carcinoma.

Since you found that a mountain was named for my work in western Antarctica, here is the mountain for you to explore!

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